Submissions for variant NM_000546.5(TP53):c.577C>T (p.His193Tyr) (rs876658468)

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221478	SCV000273726	likely pathogenic	Hereditary cancer-predisposing syndrome	2014-11-17	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Database of Curated Mutations (DoCM)	RCV000418749	SCV000508486	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429902	SCV000508487	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440111	SCV000508488	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419839	SCV000508489	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430089	SCV000508490	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441207	SCV000508491	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423524	SCV000508492	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434647	SCV000508493	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441502	SCV000508494	likely pathogenic	Small cell lung cancer	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421204	SCV000508495	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431464	SCV000508496	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445008	SCV000508497	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424900	SCV000508498	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432551	SCV000508499	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444740	SCV000508500	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425998	SCV000508501	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436284	SCV000508502	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419469	SCV000508503	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426264	SCV000508504	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437380	SCV000508505	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
GeneDx	RCV000412758	SCV000491082	likely pathogenic	not provided	2016-08-01	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.577C>T at the cDNA level, p.His193Tyr (H193Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in many neoplasm types according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). A study by Shiraishi et al (2004) also showed absent transactivation activity at 37 degrees Celsius, while Soubeyran et al. (2011) showed nonfunctional transactivation using a functional analysis of separated alleles in yeast (FASAY) test. TP53 His193Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 His193Tyr occurs at a position that is conserved across species and is located in DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 His193Tyr to be a likely pathogenic variant.
Invitae	RCV000809571	SCV000949726	likely pathogenic	Li-Fraumeni syndrome	2018-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 193 of the TP53 protein (p.His193Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family with Li-Fraumeni syndrome (PMID: 27328919). ClinVar contains an entry for this variant (Variation ID: 230256). This variant has been reported to affect TP53 protein function (PMID: 21514416, 14559903, 12826609). This variant disrupts the p.His193 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 7887414, 22265402, 25945745, 28724667, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.